Pharmaceutical compositions and medicaments comprising L-tryptophan, L-5-hydroxytryptophan and peripheral degradation inhibitors

Abstract

The present invention relates to the simultaneous use of L-tryptophan (L-Try) and L-5-hydroxytryptophan (5-HTP) and peripheral degradation inhibitors for the prevention and therapy of pain, depression, sleep disorders and other serotonin-dependent diseases or disorders of the CNS. All components of the medicament are to be released together. Carbidopa and / or benserazide are to be used as the peripheral degradation inhibitors for tryptophan and 5-hydroxytryptophan.

Description

[Technical field]

[0001] The present invention relates to a pharmaceutical composition or medicament comprising L-tryptophan and L-5-hydroxytryptophan and a peripheral degradation inhibitor. In particular, the present invention relates to the simultaneous use of L-tryptophan, L-5-hydroxytryptophan and at least one peripheral degradation inhibitor for the prevention and therapy of pain, depression, sleep disorders and other serotonin-dependent diseases or disorders of the CNS. [Background technology]

[0002] L-tryptophan (L-Try) and / or L-5-hydroxytryptophan (5-HTP) have been used with varying success to treat pain, depression and sleep disorders. L-tryptophan and / or L-5-hydroxytryptophan are administered in excess to thereby enhance the amount of serotonin in the CNS. However, attempts to use L-tryptophan or L-5-hydroxytryptophan alone as effective medicines are unconvincing. Despite some high dosages, activity is uncertain (high peripheral degradation / competition at the blood-brain barrier / enzyme induction, peripheral) and / or significant side effects appear (including from high serotonin augmentation / storage even in non-serotonergic neurons). Dietary experiments were performed with the exclusion of neutral amino acids that compete at the blood-brain barrier (competitive replacement).

[0003] The processing and transmission of information in the central nervous system (CNS) occurs on the basis of neurochemical transmission. The necessary messengers (neurotransmitters) are synthesized from food raw materials, usually amino acids, and then made available to the corresponding neural structures. Many diseases of the CNS are either based on a deficiency of one or more neurotransmitters in the CNS or are the result of a lack or defect in the bioavailability of neurotransmitters. Examples of such messengers include serotonin and dopamine.

[0004] Serotonin is widespread in nature and, in mammals, is found in relatively high concentrations in the CNS (hypothalamus, periaqueductal gray, central gray, limbic system), in the lungs, and in argyrophilic cells of the gastrointestinal tract.

[0005] Serotonin has peripheral effects, particularly on smooth muscle of the blood vessels of the airways and gastrointestinal tract. Serotonin has particularly significant effects on the central nervous system, where it is involved in pain management, mood control, sleep regulation, and other serotonin-dependent functions.

[0006] Dopamine is a catecholamine that occurs inter alia in the brain, the adrenal glands and sympathetic nerve endings and is a neurotransmitter of the hypophyseal stimulatory region of the hypothalamus. In Parkinson's disease, the concentration of dopamine is reduced in the nuclei of the extrapyramidal system.

[0007] Neurotransmitters such as serotonin and dopamine cannot be delivered directly to the CNS due to lack of mobility across the blood-brain barrier or significant side effects, so biochemical precursors are used.

[0008] The precursor L-DOPA is frequently administered in Parkinson's therapy to compensate for the systemic deficiency of dopamine in the CNS, especially in the basal ganglia. However, L-DOPA is already converted into a large part of the neurotransmitter that is in principle desirable in the periphery, i.e. in the blood and in the gastrointestinal tract, but also at the blood-brain barrier (BBB), and therefore does not reach the CNS, or reaches it only in insufficient amounts. Since dopamine does not move through the blood-brain barrier by itself, it flows to the periphery but practically does not enter the brain. This results in known peripheral side effects such as nausea, vomiting, cardiovascular disorders, and blood pressure changes. To reduce such side effects and increase the amount of L-DOPA available in the CNS, L-DOPA is combined with peripheral degradation inhibitors, since L-DOPA, like L-tryptophan, is degraded in the periphery by amino acid decarboxylases. As a result, L-DOPA is enriched in the plasma and can cross the blood-brain barrier in sufficiently high amounts. Here, L-DOPA is broken down into dopamine as desired. The peripheral degradation pathway of L-DOPA is partially identical to that of L-tryptophan.

[0009] The first precursor of the neurotransmitter serotonin is L-tryptophan, which is contained in most proteins at 1 to 2%. L-tryptophan occurs in the natural diet of humans and is an essential amino acid. Different pathways of L-tryptophan degradation are known. The degradation of L-tryptophan in the liver via 2-3-dioxygenase and via kynureninase is quantitatively the most important, accounting for more than 90%. In addition, there is a peripheral degradation of L-tryptophan via L-5-hydroxytryptophan (5-HTP) after decarboxylation to 5-hydroxytryptamine (5-HT = serotonin).

[0010] The peripheral degradation of L-tryptophan outside the CNS leads to the accumulation of serotonin in the wrong place, and therefore also in the periphery, leading to undesirable side effects, such as blood pressure crises, chronic diarrhea, bronchospasm, cardiac disorders, gastrointestinal disorders, etc. Only a small amount of L-tryptophan escapes peripheral degradation and can reach the CNS unhindered, where it can be degraded into the desired neurotransmitters. Attempts to administer the largest possible amount of L-tryptophan to achieve effective accumulation of this amino acid fail due to the side effects that would then appear, as well as due to the increased intracerebral and extracerebral degradation of serotonin and L-tryptophan.

[0011] In contrast, L-5-hydroxytryptophan crosses the blood-brain barrier more rapidly (direct precursor) and is therefore more difficult to apply and has more side effects, especially when combined with peripheral degradation inhibitors.

[0012] The treatment of Parkinson's disease patients with L-DOPA preparations in combination with the peripheral amino acid decarboxylase inhibitors benserazide and carbidopa, or with entacapone as an O-methyltransferase inhibitor (COMT inhibitor), is known.

[0013] The combination of L-DOPA with the specific decarboxylase inhibitor benserazide as a sustained release preparation together with hydrocolloids and some conventional excipients is described in DE-A-3232873. The relatively rapid decomposition of the active ingredient in the blood has adverse effects.

[0014] The combination of L-tryptophan with a specific decarboxylase inhibitor such as benserazide is described in EP 344158, and the combination of 5-HTP with a specific decarboxylase inhibitor such as carbidopa is described in WO 9107960.

[0015] To ensure the permanent provision of L-tryptophan at the blood-brain barrier, administration of L-tryptophan is indicated either in high concentration, or at very short intervals, or in sustained release form.From US Patent Nos. 4,126,672, 4,140,755, 4,167,558 and the above-mentioned German Patent Application No. 3,232,873, preparations are known that show sustained release when applied orally.These are capsules or tablets that are hydrodynamically balanced to have a specific gravity of less than 1, and will float in gastric juice with a specific gravity of 1.0004 to 1.010.The sustained drug release of these preparations is based on a mixture of active ingredient with one or more hydrophilic hydrocolloids.

[0016] The combination of L-tryptophan and peripheral degradation inhibitors such as benserazide and carbidopa in sustained release form for the treatment of pain is described in EP 0344158. Since the relatively rapid decomposition (short plasma half-life) of benserazide and carbidopa in plasma is known, sustained release of both L-tryptophan and peripheral degradation inhibitors in a specific dosage form is described. In this, the permanent availability of L-tryptophan (in sustained release form) at the blood-brain barrier is supported by the permanent availability of peripheral degradation inhibitors (benserazide or carbidopa, also in sustained release form).

[0017] In the hope of fewer side effects, improved tolerability and a simpler galenic formulation, the sustained release of peripheral degradation inhibitors (benserazide and carbidopa) has been omitted in EP 1 784 177, so the present disclosure still relates to the sustained release of L-tryptophan and no longer to the sustained release of benserazide and carbidopa.

[0018] The use of L-tryptophan or L-5-hydroxytryptophan in combination with benserazide and the associated low dosages of L-tryptophan or L-5-hydroxytryptophan has been described by F. Sicuteri in "Advances in Pain Research and Therapy" Vol. 1, 1976. These combinations have significant drawbacks from the point of view of their galenical formulation, in particular the combination of L-tryptophan with benserazide shows a significant delay in the onset of its analgesic effect of at least 2 weeks.

[0019] Administration of L-tryptophan as well as L-5-hydroxytryptophan (a metabolite of L-tryptophan) increases central serotonin metabolism and serotonin concentration in the CNS. Increasing serotonin concentration can be used in therapy or prevention, particularly for pain, depression, sleep disorder and other serotonin-dependent diseases of the CNS. L-tryptophan is a physiological compound (essential amino acid) that can be used to treat, for example, sleep disorder, depression, pain and other serotonin-dependent complaints or diseases. Summary of the Invention

[0020] The present invention relates to a pharmaceutical composition or medicament comprising L-tryptophan (L-Try), L-5-hydroxytryptophan (5-HTP) and at least one peripheral degradation inhibitor for the prevention and therapy of pain, depression, sleep disorders and other serotonin-dependent diseases or disorders of the CNS, which composition or medicament provides a very rapid onset of analgesic effect of about 5 days.

[0021] Based on the findings of the inventors, the essential feature of the present invention is the use of another active ingredient in the form of L-5-hydroxytryptophan in addition to tryptophan. L-5-hydroxytryptophan is a metabolic product of L-tryptophan and a direct precursor of serotonin. In contrast to L-tryptophan, L-5-hydroxytryptophan can cross the blood-brain barrier (BBB) ​​quickly and does not compete with other neutral amino acids at the BBB, but is more difficult to handle due to more severe side effects, especially when combined with peripheral degradation inhibitors such as benserazide or carbidopa. L-tryptophan and L-5-hydroxytryptophan have been known for a long time by themselves and have also been used as drugs in humans. Also known is the use of benserazide and carbidopa in combination with L-tryptophan or L-5-hydroxytryptophan. It is also known that L-tryptophan and L-5-hydroxytryptophan act at different speeds due to different mechanisms of uptake into the CNS, and are associated with different side effects and risks. L-tryptophan is taken up more slowly into the CNS and acts more slowly, but is safer in sustained mode when combined with peripheral degradation inhibitors. L-5-hydroxytryptophan is taken up more quickly into the CNS and acts more quickly, is more potent, but is also more dangerous and is more difficult to handle when combined with peripheral degradation inhibitors. However, it was unexpected that the combination of L-tryptophan, L-5-hydroxytryptophan and degradation inhibitors provided a much earlier onset of analgesic effect than a composition without the addition of L-5-hydroxytryptophan. Thus, the present invention provides (1) A pharmaceutical composition or medicament comprising L-tryptophan or a pharma- ceutically acceptable salt thereof, L-5-hydroxytryptophan or a pharma- ceutically acceptable salt thereof, and at least one peripheral degradation inhibitor, said pharmaceutical composition or medicament being particularly suitable for use in the prophylaxis and therapy of pain, depression, sleep disorders and other serotonin-dependent diseases or disorders of the CNS; (2) A composition comprising L-tryptophan or a pharma- ceutically acceptable salt thereof, L-5-hydroxytryptophan or a pharma- ceutically acceptable salt thereof, and at least one peripheral degradation inhibitor for use in the prophylaxis and therapy of pain, depression, sleep disorders, and other serotonin-dependent diseases or disorders of the CNS; or (3) A method for the prevention and therapy of pain, depression, sleep disorders and other serotonin-dependent diseases or disorders of the CNS in a subject, comprising the step of administering to a subject in need of such treatment a composition comprising L-tryptophan or a pharma- ceutically acceptable salt thereof, L-5-hydroxytryptophan or a pharma- ceutically acceptable salt thereof, and at least one peripheral degradation inhibitor. to provide.

[0022] The (pharmaceutical) composition, medicament or method of the invention as defined herein above is suitable for the simultaneous uptake of L-tryptophan and L-5-hydroxytryptophan in combination with at least one peripheral degradation inhibitor, such as benserazide or carbidopa, preferably in sustained release form, for the treatment of pain, depression, sleep disorders or other serotonin-dependent diseases of the CNS.

[0023] By simultaneous use of L-tryptophan and L-5-hydroxytryptophan, for example in combination with benserazide or carbidopa, and due to the different metabolic mechanisms of the different components with their advantages and disadvantages, enhanced efficacy and fewer side effects should be considered compared to previously used dosage forms. In addition, the simultaneous use of L-5-hydroxytryptophan results in an earlier onset of activity. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] In the (pharmaceutical) composition, medicament or method of the invention as defined hereinbefore, the weight ratio of L-tryptophan to L-5-hydroxytryptophan may be set to almost any value. In the following, when L-tryptophan and L-5-hydroxytryptophan are mentioned, this includes the respective pharmaceutical acceptable salts of said compounds, such as sodium salts. However, particularly preferred according to the invention are (pharmaceutical) compositions or medicaments in which the weight ratio of L-tryptophan to L-5-hydroxytryptophan is from 20:1 to 1:1. All components of the (pharmaceutical) composition or medicament according to the invention are to be released together if possible. In particular, carbidopa and / or benserazide are to be used as said peripheral degradation inhibitors for tryptophan and L-5-hydroxytryptophan.

[0025] The combination of L-tryptophan in sustained release form (retarded formulation) with peripheral degradation inhibitor of tryptophan is of great importance for the treatment of the diseases mentioned above, due to the mechanism of uptake through the blood-brain barrier.Preferably, amino acid decarboxylase inhibitor and / or kynureninase inhibitor and / or tryptophan-2-3-dioxygenase inhibitor are used as peripheral degradation inhibitor for L-tryptophan in the present invention.Benserazide and carbidopa are most preferably used.

[0026] It is particularly preferred according to the present invention that the (pharmaceutical) composition or medicament comprises L-tryptophan in a sustained release dosage form. Sustained release dosage forms for L-tryptophan are known per se to those skilled in the art. Sustained release of L-5-hydroxytryptophan is possible in the same manner.

[0027] Alternatively or additionally, the (pharmaceutical) composition or medicament according to the invention may contain L-5-hydroxytryptophan in a sustained release dosage form. Thus, particularly preferred (pharmaceutical) compositions or medicaments contain L-tryptophan in a sustained release dosage form and L-5-hydroxytryptophan in a sustained release dosage form.

[0028] It is particularly preferred according to the invention for the (pharmaceutical) composition or medicament to comprise a weight ratio of tryptophan and L-5-hydroxytryptophan to peripheral degradation inhibitor of from 20:1 to 1:1, in particular from 3:1 to 5:1.

[0029] In the (pharmaceutical) composition or medicament according to the invention, the peripheral degradation inhibitor is preferably selected from (2S)-3-(3,4-dihydroxyphenyl)-2-hydrazino-2-methylpropionic acid (carbidopa) or DL-serine-2-(2,3,4-trihydroxybenzyl)hydrazide hydrochloride (benserazide), and mixtures thereof.Therefore, the (pharmaceutical) composition or medicament according to the invention containing carbidopa and benserazide is particularly preferred.

[0030] The (pharmaceutical) composition or medicament according to the present invention may further comprise one or more pharma- ceutically acceptable carriers, binders, disintegrants, solvents, flavorings, taste masking agents, coloring agents, etc., depending on the dosage form.

[0031] The peripheral degradation inhibitor(s) may be contained in a non-sustained release dosage form or in a sustained release dosage form.

[0032] The galenic dosage form can be realized in almost any form, for example, capsules, tablets, liquids or inhalants.

[0033] The peripheral degradation inhibitor may be administered simultaneously with L-tryptophan.

[0034] The present invention is further described in the following examples, which should not be construed as limiting the invention. EXAMPLES

[0035] [Example 1] (Comparative Example) Two studies were conducted not according to the invention using sustained release L-tryptophan and sustained release benserazide.

[0036] First study: In the Weserland-Klinik hospital in Bad Seebruch / Vlotho, Germany. Title: Analgetic with sustained release in patients with fibromyalgia (L-tryptophan in combination with a peripheral degradation inhibitor, here benserazide), 2004. 22 subjects (12 verum, 10 placebo), double-blind, randomized. Results: Effects appeared after two weeks, and pain was reduced by approximately 45% after four weeks.

[0037] Second study: Outpatient Pain Department of the Jacobi Krankenhaus hospital in Rheine, Germany. Title: Treatment of chronic pain with a combination drug consisting of L-tryptophan and benserazide (sustained release), 2001. 36 subjects (18 real drug, 18 placebo), double-blind, randomized. Results: Effects appeared after two weeks, and pain was reduced by approximately 45% after four weeks.

[0038] To model non-sustained release uptake of benserazide, another mini-study was performed using three doses of benserazide and only five subjects. The results were similar.

[0039] result:In addition to the excellent analgesic effect attributable to L-tryptophan, studies have shown that continuous administration of L-tryptophan (corresponding to sustained release administration) is required for optimal effect and consistently high plasma levels. In addition, studies have shown that sustained release administration of benserazide is useful but not essential to achieve efficacy.

[0040] On the downside, the onset of effect was unfortunately surprisingly slow, i.e. only after about two weeks.

[0041] [Example 2] formulation: (a) 1 capsule / tablet: 600 mg L-tryptophan and 62.5 mg benserazide, delayed, and 50 mg L-5-hydroxytryptophan, non-retarded. 1 to 2 capsules / tablets in the morning and 1 in the evening. (b) 1 capsule / tablet: 600 mg L-tryptophan and 62.5 mg benserazide, delayed, and 50 mg L-5-hydroxytryptophan, delayed.

[0042] the study: One to two capsules / tablets in the morning and one in the evening, respectively, were shown to provide an early onset of analgesic effect after about 5 days and a pain reduction of about 45% after 2 weeks, regardless of the delay applied for both formulations (a) and (b), i.e., L-5-hydroxytryptophan.

Claims

1. A pharmaceutical composition or medicament comprising L-tryptophan or a pharmaceutically acceptable salt thereof, L-5-hydroxytryptophan or a pharmaceutically acceptable salt thereof, and at least one peripheral degradation inhibitor, the pharmaceutical composition or medicament comprising said L-tryptophan or a pharmaceutically acceptable salt thereof in a sustained-release dosage form.

2. 2. The pharmaceutical composition or medicament of claim 1, wherein the weight ratio of L-tryptophan to L-5-hydroxytryptophan is from 20:1 to 1:

1.

3. The pharmaceutical composition or medicament described in claim 1, which contains the L-5-hydroxytryptophan or a pharmaceutically acceptable salt thereof in a sustained release dosage form.

4. 2. The pharmaceutical composition or medicament of claim 1, comprising L-tryptophan in a sustained release dosage form and L-5-hydroxytryptophan in a non-sustained release dosage form.

5. 2. The pharmaceutical composition or medicament according to claim 1, wherein the weight ratio of the sum of tryptophan and L-5-hydroxytryptophan to the peripheral degradation inhibitor is from 20:1 to 1:

1.

6. 2. The pharmaceutical composition or medicament of claim 1, wherein the peripheral degradation inhibitor is selected from the group consisting of (2S)-3-(3,4-dihydroxyphenyl)-2-hydrazino-2-methylpropionic acid (carbidopa), DL-serine-2-(2,3,4-trihydroxybenzyl)hydrazide hydrochloride (benserazide), and mixtures thereof.

7. 7. A pharmaceutical composition or medicament according to claim 6, comprising carbidopa and benserazide.

8. (i) at least one of said peripheral degradation inhibitors in a non-sustained release dosage form; or (ii) at least one of said peripheral degradation inhibitors in sustained release dosage form; The pharmaceutical composition or medicament according to claim 1, comprising:

9. 10. The pharmaceutical composition or medicament of claim 1, further comprising one or more pharmaceutically acceptable carriers, binders, disintegrants, solvents, flavoring agents, taste masking agents and / or coloring agents.

10. (i) in the form of a capsule, tablet, liquid, or inhalant; and / or (ii) A pharmaceutical composition or medicament according to claim 1, which is suitable for simultaneous ingestion of L-tryptophan, L-5-hydroxytryptophan and said at least one peripheral degradation inhibitor.

11. 11. A pharmaceutical composition or medicament according to any one of claims 1 to 10 for use in the prevention and therapy of pain, depression, sleep disorders and other serotonin-dependent diseases or disorders of the CNS.

12. A composition comprising L-tryptophan or a pharmaceutically acceptable salt thereof, L-5-hydroxytryptophan or a pharmaceutically acceptable salt thereof, and at least one peripheral degradation inhibitor for use in the prevention and therapy of pain, depression, sleep disorders, and other serotonin-dependent diseases or disorders of the CNS, wherein the composition comprises the L-tryptophan or a pharmaceutically acceptable salt thereof in a sustained release dosage form.

13. 13. A composition for use in the prevention and therapy of pain, depression, sleep disorders and other serotonin-dependent diseases or disorders of the CNS according to claim 12, comprising: (i) as defined in any one of claims 2 to 10; and / or (ii) A composition suitable for simultaneous ingestion of L-tryptophan, L-5-hydroxytryptophan and said at least one peripheral degradation inhibitor.

14. 1. Use of L-tryptophan or a pharmaceutically acceptable salt thereof, L-5-hydroxytryptophan or a pharmaceutically acceptable salt thereof, and at least one peripheral degradation inhibitor in the manufacture of a medicament for the prevention and therapy of pain, depression, sleep disorders, and other serotonin-dependent diseases or disorders of the CNS, wherein the medicament comprises a sustained-release dosage form of the L-tryptophan or a pharmaceutically acceptable salt thereof.

15. (i) the medicament is as defined in any one of claims 2 to 10, and / or (ii) The use according to claim 14, wherein the medicament is suitable for simultaneous intake of L-tryptophan and L-5-hydroxytryptophan and the at least one peripheral degradation inhibitor.